Anthocyanidins occur widely in nature, and are responsible for the characteristic dark pigmentations of several members of the plant kingdom. Importantly, they are known for their anti-cancer activity. Very recently, for example, cyanidin-3-rutinoside, an extract of black raspberries, has been shown to kill leukemic cells in vitro while leaving healthy cells unharmed. Moreover, studies at the molecular level have revealed that anthocyanidins exert their cancer chemopreventive activity by several different mechanisms. The objectives of this proposal are to develop a new route to the cyanidin framework and extend this methodology to the synthesis of several nitrogen heterocyclic motifs. This will involve trapping arynes such as benzyne with electron-rich enones and enimines to generate intermediates that can be converted to either a cyanidin or quinolinium salt by an elimination step. A number of arynes will be generated from their 2-(trimethylsilyl)phenyl triflate or benzenediazonium-2-carboxylate precursors, according to literature procedures. If cyanidin synthesis is successful, attention will focus on developing a strategy that will allow the incorporation of a sugar moiety at the 3-position, and hence permit anthocyanidin synthesis. In the event that enimines prove to be superior agents for trapping arynes, the synthesis of 2-aryl-substituted quinolines, 4-quinolones, and quinolinequinones from quinolinium salts will take priority. 2-Aryl-substituted quinolines are known to possess a broad range of biological activities including anti-cancer effects. However, very few methoxy-substituted derivatives have been reported. The proposed Diels-Alder route to quinolinium salts would be ideally suited for preparing quinoline derivatives containing highly oxygenated pharmacophores. These novel derivatives will be prepared by demethylating their N-methyl quinolinium salts with triphenylphosphine. Minor modifications to this route should also provide access to a series of novel, methoxy-substituted quinolinequinones. Finally, with judicious choice of donor in the Diels-Alder step, we will exploit this methodology to synthesize highly oxygenated 2-aryl-substituted 4-quinolone derivatives. Both Quinolinequinones and 4-quinolones have been studied for their antitumor potential. PUBLIC HEALTH RELEVANCE: This project proposes to develop new synthetic strategies for preparing several potentially medicinally-active compounds that could serve as lead compounds for cancer therapy. These compounds include natural products, such as anthocyanidins found in the darkly pigmented skins of berries, as well as unnatural derivatives of quinoline and related substances.